Project Summary Alzheimer?s disease (AD) is an age-related progressive neurodegenerative disease of the central nervous system, and the most common cause of dementia, characterized by a progressive loss of cognitive function and behavioral disorders. Currently, there is no approved treatment for AD. Therefore, there is an increasing interest in identifying modifiable risk factors for AD, aiming to develop preventive strategies that could lower AD prevalence and ameliorate the clinical manifestations of AD. It has been suggested that neuroinflammation is important in the development and progression of neurodegeneration observed in AD. Aging is a complex multifactorial process that increases the susceptibility to chronic microbial infections and inflammatory diseases, such as periodontitis, a bacteria-mediated chronic inflammatory disorder characterized by the loss of alveolar bone. In recent years, increasing evidence suggests that periodontal disease is a contributing factor to AD. However, studies clearly demonstrating a causal relationship between periodontal infection and the development of AD-associated neuropathology are missing. The objective of this one year, pilot project is to delineate the effect of periodontal pathogen Porphyromonas gingivalis (Pg) infection on the development of AD. We will use two AD mouse models with cognitive deficits in different behavior paradigms: the APP/PS1 transgenic mouse model and the APPNL-G-F/NL-G-F knock-in mouse model. We hypothesize that Pg infection influences the onset and progression of both neurodegeneration and cognitive deficits by enhancing neuroinflammation. Our proposed studies will provide novel and significant insight into the association between periodontal disease and AD, consequently resulting in the identification of potential preventive interventions for AD.